Correlation of red marrow radiation dosimetry with myelotoxicity

Empirical factors influencing the radiation-induced myelotoxicity of radiolabeled antibodies, fragments and peptides in pre-clinical and clinical settings

Thomas M. Behr, Martin Béhé, George Sgouros

Research output: Contribution to journalArticle

Abstract

Usually, the red marrow (RM) is the first dose-limiting organ in systemic radionuclide therapy, e.g., radioimmunoor radiopeptide therapy. However, several studies have obtained rather poor correlations between the marrow doses and the resulting toxicities. Red marrow doses are mostly not determined directly, but are derived from blood or whole-body doses. The aim of our recent work was to analyze, in a nude mouse model in more detail, additional factors than just total dose, such as dose rate or relative biological effectiveness (RBE) factors, that may influence the resulting myelotoxicity. Furthermore, we wanted to analyze, whether correlations between the red marrow doses and the resulting myelotoxicities can be found in clinical metabolic endo-radiotherapy. The maximum tolerated activities (MTAs) and doses (MTDs) of several murine, chimeric and humanized immunoconjugates as complete IgG or fragments (F(ab)2, Fab), as well as peptides, labeled with β--(such as 131I or 90Y), Auger electron- (such as 125I or 111In), or α-emitters (such as 213Bi) were determined in nude mice. Blood counts were monitored at weekly intervals; bone marrow transplantation (BMT) was performed in order to support the assumption of the RM as dose-limiting. The radiation dosimetry was derived from biodistribution data of the various conjugates, accounting for cross-organ radiation; the activities in the blood, bone, bone marrow, and major organs were determined over time. Dosimetry and myelotoxicity data of three clinical radioimmunotherapy trials, involving a total of 82 colorectal cancer patients, treated with 131I-labeled anti-CEA IgG, and twelve non-Hodgkin's lymphoma patients, treated with 131I-labeled anti-CD20 IgG, were analyzed. In the preclinical model, at the respective MTAs, the RM doses differed significantly between the three conjugates: e.g., with 131I-labeled conjugates, the maximum tolerated activities were 260 μCi for IgG, 1200 μCi for F(ab)2, and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy, and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG, and still 3 times higher as compared to F(ab)2; interestingly, all 3 deliver ∼4 Gy within the first 24 h. The MTDs of all three conjugates were increased by BMT by approximately 30%. Similar observations were made for the 90Y-labeled conjugates. Higher blood-based RM doses were tolerated with Auger-emitters than with conventional β--emitters, whereas the MTDs were similar between α- and β--emitters. In accordance to dose rates never exceeding those occurring at the single injection MTA, re-injections of 131I-, 90Y-, or 213Bi-labeled Fab' were tolerated without increased lethality, if administered 24-48 h apart, whereas reinjection of bivalent conjugates was not possible. Clinically, a sigmoidally shaped dose-effect correlation was found in colorectal cancer patients treated with 131I-anti-CEA IgG. Previous mitomycin chemotherapy was identified as additional myelosensitizing factor leading to enhanced myelotoxicity. At comparable doses, non-Hodgkin's lymphoma patients developed higher degrees of myelotoxicity with a less clearly pronounced predictability from red marrow doses. In summary, results in the murine model suggest a strong influence of the dose rate (or better: dose per unit time), not only total dose on the resulting myelotoxicity, whereas the influence of high- (α, Auger/conversion electrons) versus low-LET (β,γ) type radiation seems to be much lower than expected from previous in vitro data. The lower myelotoxicity of Auger e- emitters is probably due to the short path length of their low-energy electrons, which cannot reach the nuclear DNA if the antibody is not internalized into the stem cells of the red marrow. Clinically, additional factors than just marrow dose (e.g., previous myelotoxic therapy, bone marrow involvement by metastatic malignancy) seem to affect the resulting myelotoxicity.

Original languageEnglish (US)
Pages (from-to)445-464
Number of pages20
JournalCancer Biotherapy and Radiopharmaceuticals
Volume17
Issue number4
StatePublished - 2002
Externally publishedYes

Fingerprint

Radiometry
Immunoglobulin Fragments
Bone Marrow
Radiation
Peptides
Pemetrexed
Immunoglobulin G
Electrons
Bone Marrow Transplantation
Nude Mice
Non-Hodgkin's Lymphoma
Colorectal Neoplasms
Relative Biological Effectiveness
Immunoconjugates
Radioimmunotherapy
Linear Energy Transfer
Injections
Maximum Tolerated Dose
Biological Factors
Mitomycin

Keywords

  • Alpha emitters
  • Auger/conversion electron emitters
  • Beta emitters
  • Dose rate
  • IgG
  • Linear energy transfer (LET)
  • Monoclonal antibody
  • Myelotoxicity
  • Radioimmunotherapy
  • Radiopeptide therapy
  • Red marrow dosimetry
  • Relative biological effectiveness (RBE) factor

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

@article{7d52f5e0d6fe4173b6bcd04bdecc2668,
title = "Correlation of red marrow radiation dosimetry with myelotoxicity: Empirical factors influencing the radiation-induced myelotoxicity of radiolabeled antibodies, fragments and peptides in pre-clinical and clinical settings",
abstract = "Usually, the red marrow (RM) is the first dose-limiting organ in systemic radionuclide therapy, e.g., radioimmunoor radiopeptide therapy. However, several studies have obtained rather poor correlations between the marrow doses and the resulting toxicities. Red marrow doses are mostly not determined directly, but are derived from blood or whole-body doses. The aim of our recent work was to analyze, in a nude mouse model in more detail, additional factors than just total dose, such as dose rate or relative biological effectiveness (RBE) factors, that may influence the resulting myelotoxicity. Furthermore, we wanted to analyze, whether correlations between the red marrow doses and the resulting myelotoxicities can be found in clinical metabolic endo-radiotherapy. The maximum tolerated activities (MTAs) and doses (MTDs) of several murine, chimeric and humanized immunoconjugates as complete IgG or fragments (F(ab)2, Fab), as well as peptides, labeled with β--(such as 131I or 90Y), Auger electron- (such as 125I or 111In), or α-emitters (such as 213Bi) were determined in nude mice. Blood counts were monitored at weekly intervals; bone marrow transplantation (BMT) was performed in order to support the assumption of the RM as dose-limiting. The radiation dosimetry was derived from biodistribution data of the various conjugates, accounting for cross-organ radiation; the activities in the blood, bone, bone marrow, and major organs were determined over time. Dosimetry and myelotoxicity data of three clinical radioimmunotherapy trials, involving a total of 82 colorectal cancer patients, treated with 131I-labeled anti-CEA IgG, and twelve non-Hodgkin's lymphoma patients, treated with 131I-labeled anti-CD20 IgG, were analyzed. In the preclinical model, at the respective MTAs, the RM doses differed significantly between the three conjugates: e.g., with 131I-labeled conjugates, the maximum tolerated activities were 260 μCi for IgG, 1200 μCi for F(ab)2, and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy, and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG, and still 3 times higher as compared to F(ab)2; interestingly, all 3 deliver ∼4 Gy within the first 24 h. The MTDs of all three conjugates were increased by BMT by approximately 30{\%}. Similar observations were made for the 90Y-labeled conjugates. Higher blood-based RM doses were tolerated with Auger-emitters than with conventional β--emitters, whereas the MTDs were similar between α- and β--emitters. In accordance to dose rates never exceeding those occurring at the single injection MTA, re-injections of 131I-, 90Y-, or 213Bi-labeled Fab' were tolerated without increased lethality, if administered 24-48 h apart, whereas reinjection of bivalent conjugates was not possible. Clinically, a sigmoidally shaped dose-effect correlation was found in colorectal cancer patients treated with 131I-anti-CEA IgG. Previous mitomycin chemotherapy was identified as additional myelosensitizing factor leading to enhanced myelotoxicity. At comparable doses, non-Hodgkin's lymphoma patients developed higher degrees of myelotoxicity with a less clearly pronounced predictability from red marrow doses. In summary, results in the murine model suggest a strong influence of the dose rate (or better: dose per unit time), not only total dose on the resulting myelotoxicity, whereas the influence of high- (α, Auger/conversion electrons) versus low-LET (β,γ) type radiation seems to be much lower than expected from previous in vitro data. The lower myelotoxicity of Auger e- emitters is probably due to the short path length of their low-energy electrons, which cannot reach the nuclear DNA if the antibody is not internalized into the stem cells of the red marrow. Clinically, additional factors than just marrow dose (e.g., previous myelotoxic therapy, bone marrow involvement by metastatic malignancy) seem to affect the resulting myelotoxicity.",
keywords = "Alpha emitters, Auger/conversion electron emitters, Beta emitters, Dose rate, IgG, Linear energy transfer (LET), Monoclonal antibody, Myelotoxicity, Radioimmunotherapy, Radiopeptide therapy, Red marrow dosimetry, Relative biological effectiveness (RBE) factor",
author = "Behr, {Thomas M.} and Martin B{\'e}h{\'e} and George Sgouros",
year = "2002",
language = "English (US)",
volume = "17",
pages = "445--464",
journal = "Cancer Biotherapy and Radiopharmaceuticals",
issn = "1084-9785",
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}

TY - JOUR

T1 - Correlation of red marrow radiation dosimetry with myelotoxicity

T2 - Empirical factors influencing the radiation-induced myelotoxicity of radiolabeled antibodies, fragments and peptides in pre-clinical and clinical settings

AU - Behr, Thomas M.

AU - Béhé, Martin

AU - Sgouros, George

PY - 2002

Y1 - 2002

N2 - Usually, the red marrow (RM) is the first dose-limiting organ in systemic radionuclide therapy, e.g., radioimmunoor radiopeptide therapy. However, several studies have obtained rather poor correlations between the marrow doses and the resulting toxicities. Red marrow doses are mostly not determined directly, but are derived from blood or whole-body doses. The aim of our recent work was to analyze, in a nude mouse model in more detail, additional factors than just total dose, such as dose rate or relative biological effectiveness (RBE) factors, that may influence the resulting myelotoxicity. Furthermore, we wanted to analyze, whether correlations between the red marrow doses and the resulting myelotoxicities can be found in clinical metabolic endo-radiotherapy. The maximum tolerated activities (MTAs) and doses (MTDs) of several murine, chimeric and humanized immunoconjugates as complete IgG or fragments (F(ab)2, Fab), as well as peptides, labeled with β--(such as 131I or 90Y), Auger electron- (such as 125I or 111In), or α-emitters (such as 213Bi) were determined in nude mice. Blood counts were monitored at weekly intervals; bone marrow transplantation (BMT) was performed in order to support the assumption of the RM as dose-limiting. The radiation dosimetry was derived from biodistribution data of the various conjugates, accounting for cross-organ radiation; the activities in the blood, bone, bone marrow, and major organs were determined over time. Dosimetry and myelotoxicity data of three clinical radioimmunotherapy trials, involving a total of 82 colorectal cancer patients, treated with 131I-labeled anti-CEA IgG, and twelve non-Hodgkin's lymphoma patients, treated with 131I-labeled anti-CD20 IgG, were analyzed. In the preclinical model, at the respective MTAs, the RM doses differed significantly between the three conjugates: e.g., with 131I-labeled conjugates, the maximum tolerated activities were 260 μCi for IgG, 1200 μCi for F(ab)2, and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy, and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG, and still 3 times higher as compared to F(ab)2; interestingly, all 3 deliver ∼4 Gy within the first 24 h. The MTDs of all three conjugates were increased by BMT by approximately 30%. Similar observations were made for the 90Y-labeled conjugates. Higher blood-based RM doses were tolerated with Auger-emitters than with conventional β--emitters, whereas the MTDs were similar between α- and β--emitters. In accordance to dose rates never exceeding those occurring at the single injection MTA, re-injections of 131I-, 90Y-, or 213Bi-labeled Fab' were tolerated without increased lethality, if administered 24-48 h apart, whereas reinjection of bivalent conjugates was not possible. Clinically, a sigmoidally shaped dose-effect correlation was found in colorectal cancer patients treated with 131I-anti-CEA IgG. Previous mitomycin chemotherapy was identified as additional myelosensitizing factor leading to enhanced myelotoxicity. At comparable doses, non-Hodgkin's lymphoma patients developed higher degrees of myelotoxicity with a less clearly pronounced predictability from red marrow doses. In summary, results in the murine model suggest a strong influence of the dose rate (or better: dose per unit time), not only total dose on the resulting myelotoxicity, whereas the influence of high- (α, Auger/conversion electrons) versus low-LET (β,γ) type radiation seems to be much lower than expected from previous in vitro data. The lower myelotoxicity of Auger e- emitters is probably due to the short path length of their low-energy electrons, which cannot reach the nuclear DNA if the antibody is not internalized into the stem cells of the red marrow. Clinically, additional factors than just marrow dose (e.g., previous myelotoxic therapy, bone marrow involvement by metastatic malignancy) seem to affect the resulting myelotoxicity.

AB - Usually, the red marrow (RM) is the first dose-limiting organ in systemic radionuclide therapy, e.g., radioimmunoor radiopeptide therapy. However, several studies have obtained rather poor correlations between the marrow doses and the resulting toxicities. Red marrow doses are mostly not determined directly, but are derived from blood or whole-body doses. The aim of our recent work was to analyze, in a nude mouse model in more detail, additional factors than just total dose, such as dose rate or relative biological effectiveness (RBE) factors, that may influence the resulting myelotoxicity. Furthermore, we wanted to analyze, whether correlations between the red marrow doses and the resulting myelotoxicities can be found in clinical metabolic endo-radiotherapy. The maximum tolerated activities (MTAs) and doses (MTDs) of several murine, chimeric and humanized immunoconjugates as complete IgG or fragments (F(ab)2, Fab), as well as peptides, labeled with β--(such as 131I or 90Y), Auger electron- (such as 125I or 111In), or α-emitters (such as 213Bi) were determined in nude mice. Blood counts were monitored at weekly intervals; bone marrow transplantation (BMT) was performed in order to support the assumption of the RM as dose-limiting. The radiation dosimetry was derived from biodistribution data of the various conjugates, accounting for cross-organ radiation; the activities in the blood, bone, bone marrow, and major organs were determined over time. Dosimetry and myelotoxicity data of three clinical radioimmunotherapy trials, involving a total of 82 colorectal cancer patients, treated with 131I-labeled anti-CEA IgG, and twelve non-Hodgkin's lymphoma patients, treated with 131I-labeled anti-CD20 IgG, were analyzed. In the preclinical model, at the respective MTAs, the RM doses differed significantly between the three conjugates: e.g., with 131I-labeled conjugates, the maximum tolerated activities were 260 μCi for IgG, 1200 μCi for F(ab)2, and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy, and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG, and still 3 times higher as compared to F(ab)2; interestingly, all 3 deliver ∼4 Gy within the first 24 h. The MTDs of all three conjugates were increased by BMT by approximately 30%. Similar observations were made for the 90Y-labeled conjugates. Higher blood-based RM doses were tolerated with Auger-emitters than with conventional β--emitters, whereas the MTDs were similar between α- and β--emitters. In accordance to dose rates never exceeding those occurring at the single injection MTA, re-injections of 131I-, 90Y-, or 213Bi-labeled Fab' were tolerated without increased lethality, if administered 24-48 h apart, whereas reinjection of bivalent conjugates was not possible. Clinically, a sigmoidally shaped dose-effect correlation was found in colorectal cancer patients treated with 131I-anti-CEA IgG. Previous mitomycin chemotherapy was identified as additional myelosensitizing factor leading to enhanced myelotoxicity. At comparable doses, non-Hodgkin's lymphoma patients developed higher degrees of myelotoxicity with a less clearly pronounced predictability from red marrow doses. In summary, results in the murine model suggest a strong influence of the dose rate (or better: dose per unit time), not only total dose on the resulting myelotoxicity, whereas the influence of high- (α, Auger/conversion electrons) versus low-LET (β,γ) type radiation seems to be much lower than expected from previous in vitro data. The lower myelotoxicity of Auger e- emitters is probably due to the short path length of their low-energy electrons, which cannot reach the nuclear DNA if the antibody is not internalized into the stem cells of the red marrow. Clinically, additional factors than just marrow dose (e.g., previous myelotoxic therapy, bone marrow involvement by metastatic malignancy) seem to affect the resulting myelotoxicity.

KW - Alpha emitters

KW - Auger/conversion electron emitters

KW - Beta emitters

KW - Dose rate

KW - IgG

KW - Linear energy transfer (LET)

KW - Monoclonal antibody

KW - Myelotoxicity

KW - Radioimmunotherapy

KW - Radiopeptide therapy

KW - Red marrow dosimetry

KW - Relative biological effectiveness (RBE) factor

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M3 - Article

VL - 17

SP - 445

EP - 464

JO - Cancer Biotherapy and Radiopharmaceuticals

JF - Cancer Biotherapy and Radiopharmaceuticals

SN - 1084-9785

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ER -